Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.

Abstract

The rapid clearance of circulating liposomes from the bloodstream, coupled with their high uptake by liver and spleen, has thus far been an obstacle to any attempts at targeting to tumors. We have assessed the impact of liposome composition on their clearance from the circulation in normal and tumor-bearing mice and on their uptake by tumors and various normal tissues. By selective changes in lipid composition, while maintaining a mean particle diameter of '100 nm, we have achieved up to a 60-fold increase in the fraction of recovered dose present in blood 24 hr after i.v. i 'ection. Concomitantly, there was a decrease by a factor of 4 of the recovered dose localizing in the liver and spleen, the major organs of the reticuloendothelial system. Parallel experiments in tumor-bearing mice demonstrated a 25-fold increase of the liposome concentration in the tumor when formulations with long and short blood residence time were compared. The most favorable results were obtained with liposomes containing a small molar fraction of a negatively charged glycolipid, such as monosialoganglioside or phosphatidylinositol, and a solidphase neutral phospholipid as the bulk component. The biodistribution of such formulations is of considerable therapeutic potential in cancer for increasing the concentration of cytotoxic agents in tumors while minimizLing the likelihood of toxicity to the reticuloendothelial system. Liposome encapsulation has been proven useful for reducing the toxicity of certain drugs (1-6) as well as for enhancing the efficacy of macrophage-activating factors (7,8) and drugs directed against parasites residing within the reticuloendothelial system (RES) (9)(10)(11)(12). The propensity of the RES to remove liposomes from the circulation has thus far limited the prospect oftargeting liposomes to tissues other than liver, spleen, and lung (13-15).Designing liposomes with prolonged circulation time would require a reduction of the rate of their clearance by the RES and of the leakage of liposome contents in the bloodstream. Our strategy to achieve these goals was based on the following prior observations. (i) The inclusion of cholesterol (Chol) and solid-phase phospholipids such as sphingomyelin and distearoyl phosphatidylcholine has been shown to increase liposome stability in plasma as determined by the degree of retention of various liposome-encapsulated markers in vitro (16-18). (ii) The same solid-phase phospholipids (sphingomyelin or distearoyl phosphatidylcholine) in the form of small sonicated liposomes are cleared more slowly after intravenous injection than those made with fluid phospholipids such as egg yolk phosphatidylcholine (PtdCho) (19)(20)(21)(22). (iii) The inclusion of certain gangliosides, which confer to the liposome surface a negative charge and increased hydrophilicity, synergizes with Chol to enhance liposome stability in plasma (23) and prolongs liposome half-life in blood with a concomitant decrease in liver and spleen uptake (24). In addition, inclusion of phosphatidylinositol (P...

In Vitro Evaluation of the Efficacy of Liposomal and Pegylated Liposomal Hydroxyurea

“…Pegylated liposomes covalently bind to proteins as the carrier and several lines of evidence demonstrated that pegylated therapeutic compound are more stable in circulation and are not easily removed by reticuloendothelial system (RES) and this formulation increases the adherence of drug to the cancer cell. In the other words it will result in enhancement of cellular drug absorption [9,[26][27][28][29].…”

Influence of tumour size on uptake of111In-DTPA-labelled pegylated liposomes in a human tumour xenograft model

“…Considerable research effort has gone into the optimisation of the composition of liposomes in order to achieve maximal tumour targeting (Gabizon and Papahadjopoulos, 1988;Gabizon et al, 1990;Klibanov et al 1990). However, the effect of tumour-related factors on this process has not been explored in detail.…”

“…In order to facilitate the rational integration of liposome technology into current or novel therapeutic strategies, detailed knowledge of the factors which govern liposome distribution to tumours will be required. There is a considerable amount of data in the literature examining the effect of liposomal composition on their pharmacokinetics and biodistribution (Gabizon and Papahadjopoulos, 1988;Gabizon et al, 1990;Klibanov et al, 1990). However, there is relatively little known about the influence of tumour-related factors on liposomal tumour targeting.…”

Stabilized plasmid-lipid particles: construction and characterization

“…It is now generally recognized that preferential delivery of anticancer drugs to tumor sites following intravenous injection can be achieved by encapsulation of these drugs in large unilamellar vesicles (LUVs) exhibiting a small size (Ͻ100 nm diameter) and extended circulation lifetimes (circulation half-life in mice Ͼ5 h). [7][8][9] The accumulation of these drug delivery systems at disease sites, which includes sites of infection and inflammation as well as tumors, has been attributed to enhanced permeability of the local vasculature in diseased tissue. 10 A gene delivery system containing an encapsulated plasmid for systemic applications should therefore be small (Ͻ100 nm diameter) and must exhibit extended circulation life-times to achieve enhanced delivery to disease sites.…”